title: CXCR4-SERINE339 regulates cellular adhesion, retention and mobilization, and is a marker for poor prognosis in acute myeloid leukemia.
abstract: The CXCR4 receptor is a major regulator of hematopoietic cell migration. Overexpression of CXCR4 has been associated with poor prognosis in acute myelogenous leukemia (AML). We have previously shown that ligand-mediated phosphorylation of the Serine339 (CXCR4-S339) residue of the intracellular domain by PIM1 is implicated in surface re-expression of this receptor. Here, we report that phosphorylation of CXCR4-S339 in bone marrow (BM) biopsies correlated with poor prognosis in a cohort of AML patients. To functionally address the impact of CXCR4-S339 phosphorylation, we generated cell lines-expressing CXCR4 mutants that mimic constitutive phosphorylation (S339E) or abrogate phosphorylation (S339A). Whereas the expression of CXCR4 significantly increased, both CXCR4-S339E and the CXCR4-S339A mutants significantly reduced the BM homing and engraftment of Kasumi-1 AML cells in immunodeficient mice. In contrast, only expression of the CXCR4-S339E mutant increased the BM retention of the cells and resistance to cytarabine treatment, and impaired detachment capacity and AMD3100-induced mobilization of engrafted leukemic cells. These observations suggest that the poor prognosis in AML patients displaying CXCR4-S339 phosphorylation can be the consequence of an increased retention to the BM associated with an enhanced chemoresistance of leukemic cells. Therefore, CXCR4-S339 phosphorylation could serve as a novel prognostic marker in human AML.
authors.affiliation: Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Brault
authors.affiliation: Department of Hematology, University Hospital Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Rovó
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Decker
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Dierks
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Schwaller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D012694:Serine / Q000737:chemistry*
chemical_list: D015415:Biomarkers; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D012694:Serine